Two methods of drug delivery are targeted in this competitive renewal application. In approach I, water-soluble drug candidates containing both a GalCer analog (G) and a polyanion (P) linked with a polyethylene glycol functionality will be prepared. In approach II, G and P conjugates will be templated with gp120 to assure proper ligand orientation before locking them into place through polymerization to form liposomes. Successful implementation of both drug design strategies will depend upon the identification of viable G and P candidates in forms that can readily incorporate either polyethylene glycol linkers or polymerizable lipids. GalCer analogs (G) have already been identified and conjugated to both lipids and water-soluble linkers. A procedure for identifying site specific polyanions is in place, and specific aim 1 of this renewal is directed to the identification and optimization of appropriate polyanions (P) for drug delivery. In specific aim 2, G and P conjugates, linked to donor and acceptor chromophores, will be prepared in order to determine the proximity of their binding sites on gp120. The advantages of single vs. dual ligand binding will be quantified in specific aim 3. Specific Aim 4 will utilize the information provided by specific aim 2 to prepare water-soluble G and P using a combinational approach. Specific aim 5 will utilize the information in specific aim 3 to prepare polymerizable conjugates of G and P for protein templating in liposome preparations. Specific aim 6 outlines methods for testing viable drug candidates in live cell assays. These studies will be performed on candidates identified in both ELISA and TIRF studies, including single and multiple modes of delivery to establish the correlation between studies with recombinant gp120 and intact viral particles.